Renal cell carcinoma (RCC) is the most common form of kidney cancer and responsible for approximately 80% of the kidney cancer that occur in adults. RCC represents approximately 5% of all cancer deaths and, at the time of presentation, over 50% of the patients have already developed locally advanced or metastatic disease with 5-year survival rates of less than 20%. Angiogenesis plays a crucial role in RCC tumor progression. Nascent and small tumors can obtain sufficient oxygen and nutrients to sustain their growth by simple diffusion. Beyond a diameter of 1 to 2 mm, however, diffusion cannot provide these elements in the amounts required for further growth. For growth beyond that size, all tumors require a vasculature, whatever their cause, origin, type, age, or location. Thus, tumor growth beyond a diameter of 1 to 2 mm requires angiogenesis. Angiogenesis, accordingly, has been seen as a promising target for developing an effective general treatment for tumors.
Three principal mechanisms play an important part in the activity of angiogenesis inhibitors against tumors: (i) inhibition of the growth of vessels, especially capillaries, into avascular resting tumors, with the result that there is no net tumor growth owing to the balance that is achieved between cell death and proliferation; (ii) prevention of the migration of tumor cells owing to the absence of blood flow to and from tumors; and (iii) inhibition of endothelial cell proliferation, thus avoiding the paracrine growth-stimulating effect exerted on the surrounding tissue by the endothelial cells which normally line the vessels. See R. Connell and J. Beebe, Exp. Opin. Ther. Patents, 11:77-114 (2001).
Although many signal transduction systems have been implicated in the regulation of angiogenesis, one of the best-characterized and most endothelial cell-selective systems involves the Tie2 receptor tyrosine kinase (NCBI Reference No. NP—000450.2; referred to as “Tie2” or “Tie2R” (also referred to as “ORK”); murine Tie2 is also referred to as “tek”) and its ligands, the angiopoietins (Gale, N. W. and Yancopoulos, G. D., Genes Dev. 13:1055-1066 [1999]). There are 4 known angiopoietins; angiopoietin-1 (“Ang1”) through angiopoietin-4 (“Ang4”). These angiopoietins are also referred to as “Tie2 ligands.”
Yet another important factor associated with tumor angiogenesis is vascular endothelial growth factor (VEGF). VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein related to “Platelet-Derived Growth Factor” (PDGF); it is produced by normal cell lines and tumor cell lines; is an endothelial cell-specific mitogen; shows angiogenic activity in in vivo test systems (e.g. rabbit cornea); is chemotactic for endothelial cells and monocytes; and induces plasminogen activators in endothelial cells, which are involved in the proteolytic degradation of extracellular matrix during the formation of capillaries. A number of isoforms of VEGF are known, which show comparable biological activity, but differ in the type of cells that secrete them and in their heparin-binding capacity. In addition, there are other members of the VEGF family, such as “Placental Growth Factor” (PLGF) and VEGF-C. VEGF receptors (VEGFR) are transmembranous receptor tyrosine kinases. They are characterized by an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types of VEGF receptor are known, e.g. VEGFR-1 (also known as flt-1), VEGFR-2 (also known as KDR), and VEGFR-3.
What is needed in the art is a method of predicting which human RCC patients have an increased likelihood of obtaining clinical benefit from treatment with a combination of a VEGFR inhibitor and an Ang2 inhibitor. The present invention provides this as well as other benefits.